Limitation of TCA Cycle Intermediates Represents an Oxygen-Independent Nutritional Antibacterial Effector Mechanism of Macrophages

• Published in: Cell reports (Cambridge) 2019-03, Vol.26 (13), p.3502-3510.e6
• Main Authors: Hayek, Inaya, Fischer, Fabian, Schulze-Luehrmann, Jan, Dettmer, Katja, Sobotta, Katharina, Schatz, Valentin, Kohl, Lisa, Boden, Katharina, Lang, Roland, Oefner, Peter J., Wirtz, Stefan, Jantsch, Jonathan, Lührmann, Anja
• Format: Article
• Language: English
• Subjects: Adult; Animals; Cell Hypoxia; Cells, Cultured; citrate; Citric Acid Cycle; Coxiella burnetii; Coxiella burnetii - immunology; Female; HIF1α; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - physiology; macrophage; Macrophages - immunology; Macrophages - microbiology; Male; Mice; Mice, Inbred C57BL; Middle Aged; Oxygen - metabolism; Q Fever - immunology; STAT3; STAT3 Transcription Factor - physiology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.02.103

In hypoxic and inflamed tissues, oxygen (O2)-dependent antimicrobial defenses are impaired due to a shortage of O2. To gain insight into the mechanisms that control bacterial infection under hypoxic conditions, we infected macrophages with the obligate intracellular pathogen Coxiella burnetii, the causative agent of Q fever. Our experiments revealed that hypoxia impeded C. burnetii replication in a hypoxia-inducible factor (HIF) 1α-dependent manner. Mechanistically, under hypoxia, HIF1α impaired the activity of STAT3, which in turn reduced the intracellular level of TCA cycle intermediates, including citrate, and impeded C. burnetii replication in macrophages. However, bacterial viability was maintained, allowing the persistence of C. burnetii, which is a prerequisite for the development of chronic Q fever. This knowledge will open future research avenues on the pathogenesis of chronic Q fever. In addition, the regulation of TCA cycle metabolites by HIF1α represents a previously unappreciated mechanism of host defense against intracellular pathogens. [Display omitted] •Hypoxia curtails C. burnetii replication in macrophages without reducing bacterial viability•Hypoxia induces robust HIF1α accumulation in infected macrophages•HIF1α reduces STAT3 activation and citrate availability in infected hypoxic macrophages•Low levels of TCA metabolites impede C. burnetii replication in macrophages The mechanisms that control bacterial infection under hypoxic conditions are only partially understood. Hayek et al. show that hypoxia-mediated stabilization of HIF1α results in the inhibition of STAT3 activation and the reduction of TCA metabolite levels, including citrate, in macrophages. This prevents C. burnetii replication without reducing bacterial viability.